Highlights from Recent Cancer Literature
Journal: Cancer Research (2017)

Medulloblastoma is widely classified into four molecular subgroups, however, the extent of overlap among the subgroups and the degree of heterogeneity within the subgroups is unknown. Cavalli and colleagues analyzed gene expression and DNA methylation across 763 primary medulloblastomas, integrating these data by similarity network fusion (SNF). Less than 1% of Group 3 and Group 4 tumors overlapped by SNF, arguing against these groups forming a continuum. Applying SNF clustering individually to each of the four subgroups, they identified 12 robust biological subtypes, with distinct clinical implications and cytogenetics. Infant SHH tumors comprised two groups with distinct outcomes. TP53 mutations were enriched in SHHα and portended a dismal prognosis, however, TP53 mutations outside this group fared better. Among the three Group 3 subgroups, Group 3α had frequent loss of chromosome 8q, Group 3β showed activated GFI1 oncogenes, and Group 3γ patients enriched for MYC amplicons did poorly independent of MYC status. Group 4 was comprised of three distinct groups with distinct cytogenetic aberrations. This integrated analysis provides a comprehensive overview of heterogeneity across medulloblastoma subgroups.Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 2017;31:737–54.Platinum-based chemotherapeutics exhibit dose-limiting toxicities and efficacy that is undermined by acquired resistance. By conjugating cisplatin to squalene, which spontaneously self-assemble into multilamellar nanoparticles in water, Kotelevets and colleagues provide a simple mechanism to reduce these nondesirable properties. Such nanoparticles exhibit greater efficacy in vitro than unconjugated cisplatin, reducing the viability of colon cancer cell lines, largely due to increased intracellular accumulation of the nanoparticles. The two forms of cisplatin had similar pharmacokinetics in vivo. However, because of their reduced kidney toxicity, the nanoparticles exhibited an increased maximal tolerated dose (MTD). Thus, when the two forms of cisplatin were compared at their MTD in a mouse model, the nanoparticle form exhibited significantly greater efficacy in reducing colon cancer. Further, as nanoparticle-complexed cisplatin can be administered orally, increased compliance may further improve outcomes.Kotelevets L, Chastre E, Caron J, Mougin J, Bastian G, Pineau A, et al. A squalene-based nanomedicine for oral treatment of colon cancer. Cancer Res 2017;77:2964–75.Morel and colleagues determined whether differentiation status influences cell behavior and malignant transformation following an oncogenic event. Through sorting and genetic manipulation ex vivo of breast epithelial cell populations from reduction mammoplasties, they show that only specific breast stem-cell populations tolerate oncogenic activation and thus have increased susceptibility to neoplastic transformation. Tolerance for oncogenic stimuli was traced to the ZEB1 epithelial-mesenchymal transition transcription factor. ZEB1 prevented oncogene-induced DNA damage by upregulating methionine sulfoxide reductase, a ROS-detoxifying enzyme, evidenced by lower levels of double-strand breaks and DNA damage response markers. Finally, human expression data confirmed high levels of ZEB1 in human triple-negative breast cancers, which have low frequencies of genome-wide copy number aberrations and few TP53 mutations. These novel findings further the concept that the intrinsic susceptibility of a cell to undergo malignant transformation is a unique feature of each cellular lineage and the underlying epigenetic landscape.Morel AP, Ginestier C, Pommier RM, Cabaud O, Ruiz E, Wicinski J, et al. A stemness-related ZEB1 MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nat Med 2017;23:568–78.Kamerkar and colleagues exploit exosomes as nanovehicles to deliver KRAS-dampening agents to tumor cells. Exosomes are cell-derived vesicles with a lipid membrane and membrane-embedded proteins such as CD47 that are secreted and taken up by other cells. CD47 generates a “don't eat me” signal and protects exosomes from phagocytosis within the circulation. Kamerkar and colleagues engineered exosomes (termed iExosomes), purified from normal fibroblast cultures, to carry siRNA or shRNA directed against oncogenic KRAS. In pancreatic ductal adenocarcinoma models, iExosomes effectively decreased oncogenic KRAS levels and downstream signaling, impaired tumor growth, and initiated apoptosis. These effects reduced metastasis and enhanced survival. Due to increased KRAS-mediated macropinocytosis, iExosomes preferentially localized to tumors rather than to normal tissues, suggesting an approach to directly and specifically target oncogenic KRAS in tumors.Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017;546:498–503.Although p300 has been previously implicated as a Notch coactivator, the mechanism by which it does so remains unclear. Jin and colleagues show that p300 acetylates mastermind-like protein 1 (Maml1) directly. Acetylated Maml1 recruits Notch activation complex kinase (NACK) to the Notch/Maml/CSL ternary complex. The NACK-associated ternary complex subsequently recruits RNA polymerase II to initiate transcription of Notch target genes. Interestingly, only a subset of Maml paralogs was able to recruit NACK, consistent with Maml paralogs requiring different cofactors. Simultaneous inhibition of p300 and Notch synergized to attenuate the growth of esophageal adenocarcinoma, providing a combinatorial strategy to attenuate the growth of Notch-dependent cancers.Jin K, Zhou W, Han X, Wang Z, Li B, Jeffries S, et al. Acetylation of mastermind-like 1 by p300 drives the recruitment of NACK to initiate Notch-dependent transcription. Cancer Research; Published OnlineFirst June 16, 2017; doi: 10.1158/0008-5472.CAN-16-3156.Loss of LKB1 kinase (L) in association with activated KRAS (K) portends a poor prognosis in non-small-cell lung cancer (NSCLC). Kim and colleagues now establish a reliance of KL cells and tumors on pyrimidine synthesis mediated by the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1). Transcription of CPS1 was suppressed by LKB1 through AMPK, and CPS1 expression correlated inversely with LKB1 in human NSCLC. CPS1 in KL cells catalyzed the unconventional pathway of nitrogen flow from ammonia to pyrimidines. Loss of CPS1 led to decreased pyrimidine levels, with cell death and reduced tumor growth, rather than ammonia toxicity. Surprisingly, CPS1 loss did not affect viability in L cells, suggesting that combined mutation of KRAS and LKB1 enforced this metabolic dependency. Reduced pyrimidine synthesis compromised CPS1-deficient K cells and was partially rescued by exogenous pyrimidines. These findings support a role for CPS1-mediated pyrimidine synthesis as a unique metabolic vulnerability of an aggressive subtype of NSCLC.Kim J, Hu Z, Cai L, Li K, Choi E, Faubert B, et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 2017;546:168–72.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.